Alzheimer's disease (AD) is characterized by the progressive loss of neurons in the hippocampus ultimately leading to total memory loss and death of the patient. Neuronal cell death is thought to be caused by the build-up of protein-aggregates termed "plaques" and "tangles". The role of astrocytes in neuronal cell death is only marginally understood. Most recently, we have found that astrocytes from a mouse model of AD (PS1M146V) express 9-fold higher levels of prostate apoptosis response-4 (PAR-4) than wild-type astrocytes. PAR-4 is a pro-apoptotic protein that inhibits atypical PKC6/;(aPKC) when associated with ceramide. Our main hypothesis is that elevation of PAR-4 sensitizes astrocytes toward ceramide-induced apoptosis, which leads to neurodegeneration in AD. Very exciting new results show that hippocampal tissue from the PS1 mouse is enriched in distinct ceramide species that induce apoptosis in PS1 astrocytes, but not in wild-type cells. This result clearly demonstrates that PS1 astrocytes are specifically sensitive to ceramide elevation. Further, in hippocampus from AD patients, amyloid plaques are surrounded by astrocytes that show co-elevation of ceramide and PAR-4. Many of these astrocytes are apoptotic. We will now determine how ceramide elevation is activated (Specific Aim 1), how the combined elevation of ceramide and PAR-4 induces apoptosis (Specific Aim 2), and how this co-elevation elevation and apoptosis induction can be prevented (Specific Aim 3). SIGNIFICANCE: We have shown for the first time that astrocytes from AD brain are specifically eliminated by ceramide-induced apoptosis. Using a combination of in vitro and in vivo models (Psen1 and APP/PS1 astrocytes and mice);our study will develop a novel strategy to protect astrocytes and neurons from apoptosis. This strategy will be highly significant for treatment of AD PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is a devastating disease affecting 5 million people in the United States. Progressive memory loss and ultimately, cell death of neurons is caused by the build-up of protein aggregates called "plaques" and "tangles". We have found, for the first time, that in a mouse model of AD, the lipid ceramide is enriched and specifically induces cell death in astrocytes. We hypothesize that dying astrocytes fail to support neurons, which amplifies the degeneration of neurons in AD. Our data strongly suggest that blocking the accumulation of ceramide will be instrumental in preventing loss of neurons in AD.